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Optimal Management of Methotrexate Intoxication in a Child with Osteosarcoma

Lecturer in Clinical Pharmacy, Department of Medical Pharmacology and Toxicology, Lapeyronie Hospital, Montpellier, France

Marylène Cociglio, PharmD PhD

Lecturer in Clinical Pharmacology, Department of Medical Pharmacology and Toxicology, Lapeyronie Hospital

Geneviève Margueritte, MD

Physician, Department of Pediatric Oncology, Arnaud de Villeneuve Hospital, Montpellier

Catherine Vallat, PhD

Biologist, Laboratory of Biochemistry, Saint-Eloi Hospital, Montpellier

Jean-Pierre Blayac, MD PhD

Professor in Clinical Pharmacology, Department of Medical Pharmacology and Toxicology, Lapeyronie Hospital

Dominique Hillaire-Buys, MD PhD

Lecturer in Clinical Pharmacology, Department of Medical Pharmacology and Toxicology, Lapeyronie Hospital

Reprints: Hélène Peyriere PharmD PhD, Service de Pharmacologie Médicale et Toxicologie, Hôpital Lapeyronie, 371 avenue du Doyen Gaston Giraud, 34295 Montpellier Cedex 5, France, fax 33-4-67-33-67-51, h-peyriere{at}chu-montpellier.fr

OBJECTIVE: To describe the time course and management of methotrexate (MTX) toxicity in a 14-year-old Hispanic boy with osteosarcoma treated with high-dose MTX.

CASE SUMMARY: During the sixth cycle of high-dose MTX, severe intoxication was observed with high MTX plasma concentrations, acute renal failure, and hepatitis, followed by mucositis and moderate myelosuppression. Intensification of urine alkalinization and increased leucovorin dosages did not decrease plasma concentrations of MTX or prevent systemic toxicities. Carboxypeptidase G2 and aminophylline were thus administered as a second-intention rescue strategy. Within 2 weeks, a recovery of clinical symptoms and normalization of the biological abnormalities were observed. Limb salvage surgery was performed, which permitted classifying the patient as an MTX high-responder. Thereafter, MTX was successfully resumed, leading to clinical recovery of the patient. Concomitantly, homocysteine plasma levels, a marker of the pharmacodynamic effect of MTX, were measured. During the intoxication, homocysteine plasma levels were significantly increased, parallel to the excessive MTX plasma concentrations observed.

DISCUSSION: According to the excessive MTX levels measured in this patient, along with the observed clinical (mucositis) and biological (hepatitis, renal injury) adverse effects, we suggest that MTX may be a cause of these complications. Use of the Naranjo probability scale indicated a probable relationship between the complications and MTX.

CONCLUSIONS: This observation shows that severe complications observed during one cycle of high-dose MTX is not predictive of the tolerability of further courses. Optimal management of such complications, using specific therapeutic intervention, may be considered.

Key Words: child, methotrexate, osteosarcoma

Published Online, January 23, 2004. www.theannals.com, DOI 10.1345/aph.1D237

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